PPM1D gene amplification and overexpression in breast cancer: a qRT-PCR and chromogenic in situ hybridization study

Lambros, Maryou B.; Natrajan, Rachael; Geyer, Felipe C.; López-García, María Ángeles; Dedes, Konstantin J.; Savage, Kay; Lacroix-Triki, Magali; Jones, Robin L.; Lord, Christopher J.; Linardopoulos, Spiros; Ashworth, Alan; Reis‐Filho, Jorge S.

doi:10.1038/modpathol.2010.121

Cited by 65 publications

(47 citation statements)

References 42 publications

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“…However, PPM1D amplification and/ or enhanced stabilization allow for sustained inhibition of DNA damage response proteins and numerous tumor suppressors, including ATM, Chk1 and 2, and p53. PPM1D over-expression has been implicated in a variety of human malignancies, including OVCA, and its level is directly related to poor prognosis and reduced therapeutic outcome [47][48][49][50][51][52][53][54][55][56][57].…”

Section: Discussionmentioning

confidence: 99%

Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability

Alayoud¹,

Kim²,

Pelletier

et al. 2014

Molecular Carcinogenesis

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Ovarian cancer (OVCA) and cervical cancer (CECA) are lethal gynecological malignancies. Cisplatin (CDDP) and platinum derivatives are first line chemotherapeutics and their resistance impedes successful treatment. Understanding the molecular dysregulation underlying chemoresistance is important in developing rational therapeutic strategies. We have established that Protein Phosphatase Magnesium-dependent 1 D (PPM1D) confers CDDP resistance in gynecological cancer cells by deactivating p53. However, whether CDDP regulates intra-cellular PPM1D localization and whether this regulation is different between chemosensitive and chemoresistant cancer cells is unknown. Moreover, whether Akt regulates PPM1D in the context of CDDP resistance has not been studied. To illustrate the role of PPM1D in gynecological cancer cell chemoresistance and its regulation by Akt we have demonstrated that: (a) CDDP induced PPM1D downregulation through proteasomal degradation in sensitive CECA cells; (b) CDDP induced PPM1D nuclear localization in resistant CECA cells, and nuclear exclusion in sensitive CECA cells and OVCA xenografts; (c) Over-expression of active Akt in sensitive CECA cells stabilized PPM1D content through inhibition of CDDP-induced PPM1D down-regulation; (d) Inhibition of Akt activity in resistant OVCA cells leads to decreased PPM1D stability and CDDP-induced down-regulation in resistant CECA cells; and (e) PPM1D is highly expressed in human ovarian tumor subtypes and in a tissue microarray panel of human ovarian tumors. In conclusion, we have established that PPM1D plays an important role in promoting CDDP resistance and as a novel downstream target of Akt, PPM1D mediates its action in conferring CDDP resistance in gynecological cancer cells. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.Key words: cisplatin chemoresistance; ovarian cancer; PPM1D; Akt; apoptosis INTRODUCTIONOvarian cancer (OVCA) and cervical cancer (CECA) are the most lethal gynecological malignancies. Although OVCA ranks first in the number of deaths each year, due primarily to its late diagnosis and the development of chemoresistance [1], CECA is more frequent and less deadly due to early detection. Surgical de-bulking of the tumor mass followed by adjuvant chemotherapy is the conventional course of therapy for OVCA, whereas a combination of radiation and chemotherapy is the preferred treatment regimen for CECA. Platinum derivatives, including Cisplatin (CDDP; cis-diamminedichloroplatinum) in combination with paclitaxel, are first-line chemotherapeutic agents in the treatment of these gynecologic cancers. CDDP induces apoptosis by creating inter-and intra-strand DNA adducts through irreversible intercalation, thereby inducing both the DNA damage and the apoptotic responses [2]. The majority of patients respond to chemotherapy at first, however, recurrence of the disease is a common event and tumors are usually more aggressive, metastasize to secondary target tissues, and acquire resistance to conventional chemotherape...

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Section: Discussionmentioning

confidence: 99%

Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability

Alayoud¹,

Kim²,

Pelletier

et al. 2014

Molecular Carcinogenesis

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“…Details of the methods and results of the above proteins are described elsewhere 30,31 and summarized in Supplementary Table 1. The prevalence of CCND1, HER2, TOP2A and MYC gene amplification was assessed by chromogenic in situ hybridization with SpotLight CISH probes (Invitrogen, Paisley, UK) and results not in relation to b-catenin expression were reported elsewhere.…”

Section: Immunohistochemistrymentioning

confidence: 99%

β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation

et al. 2011

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Aberrant b-catenin expression as determined by assessment of its subcellular localization constitutes a surrogate marker of Wnt signalling pathway activation and has been reported in a subset of breast cancers. The association of b-catenin/Wnt pathway activation with clinical outcome and the mechanisms leading to its activation in breast cancers still remain a matter of controversy. The aims of this study were to address the distribution of b-catenin expression in invasive breast cancers, the correlations between b-catenin expression and clinicopathological features and survival of breast cancer patients, and to determine whether aberrant b-catenin expression is driven by CTNNB1 (b-catenin encoding gene) activating mutations. Immunohistochemistry was performed on a tissue microarray containing 245 invasive breast carcinomas from uniformly treated patients, using two anti-b-catenin monoclonal antibodies. Selected samples were subjected to CTNNB1 exon 3 mutation analysis by direct gene sequencing. A good correlation between the two b-catenin antibodies was observed (Spearman's r 40.62, Po0.001). Respectively, 31 and 11% of the cases displayed lack/reduction of b-catenin membranous expression and nuclear accumulation. Complete lack of b-catenin expression was significantly associated with invasive lobular carcinoma histological type. Subgroup analysis of non-lobular cancers or non-lobular grade 3 carcinomas revealed that lack/reduction of b-catenin membranous expression and/or nuclear accumulation were significantly associated with oestrogen receptor negativity, absence of HER2 gene amplification and overexpression, lack/reduction of E-cadherin expression and tumours of triple-negative and basal-like phenotype. Univariate survival analysis revealed a significant association between b-catenin nuclear expression and shorter metastasis-free and overall survival in the whole cohort; however, b-catenin nuclear expression was not an independent predictor of outcome in multivariate analysis. No CTNNB1 mutations were identified in the 28 selected breast carcinomas analysed. In conclusion, b-catenin/Wnt pathway activation is preferentially found in triple-negative/basal-like breast carcinomas, is associated with poor clinical outcome and is unlikely to be driven by CTNNB1 mutations in breast cancer.

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“…91–94 p38α also regulates the spindle assembly checkpoint 27 and delays the G2 to M transition. 95 Important for cancer is the amplification in ~18% of human breast tumors at chromosome 17q23 of the PPM1D gene encoding the WIP1 phosphatase, 92,96 which can abrogate p38 SAPK activity. Sporadic activating mutations in PPM1D have also been described recently, suggesting multiple mechanisms for activating this p38 (and other substrates 97 ) phosphatase.…”

Section: Perk and P38 As Novel Stress-activated Regulators Of Mammarymentioning

confidence: 99%

Stress signaling and the shaping of the mammary tissue in development and cancer

2014

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The postnatal mammary gland develops extensively through cycles of proliferation, branching, involution and remodeling. We review recent advances made in the field of stress signaling pathways and its roles in mammary gland organogenesis, how they contribute to normal organ specification and homeostasis and how its subversion by oncogenes leads to cancer. We analyze stress signaling in mammary gland biology taking into account the interrelationship with the extracellular matrix and adhesion signaling during morphogenesis. By integrating the information gathered from in vivo and three dimensional in vitro organogenesis studies, we review the novel contribution of p38SAPK, c-Jun NH2-terminal kinase and PKR-like endoplasmic reticulum kinase (PERK) signaling pathways to the timely activation of cell death, correct establishment of polarity and growth arrest and autophagy, respectively. We also review the evidence supporting that the activation of the aforementioned stress kinases maintain breast acinar structures as part of a tumor suppressive program and that its deregulation is commonplace during breast cancer initiation.

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PPM1D gene amplification and overexpression in breast cancer: a qRT-PCR and chromogenic in situ hybridization study

Cited by 65 publications

References 42 publications

Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability

Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability

β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation

Stress signaling and the shaping of the mammary tissue in development and cancer

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